3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives

ABSTRACT

The present invention relates to novel compounds, in particular novel pyridinone derivatives according to Formula (I) including any stereochemically isomeric form thereof, or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein all radicals are defined in the application and claims. The compounds according to the invention are positive allosteric modulators of metabotropic glutamate receptors subtype 2 (“mGluR2”) which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. In particular, such diseases are central nervous system disorders selected from the group of anxiety, schizophrenia, migraine, depression, and epilepsy. The invention is also directed to pharmaceutical compositions and processes to prepare such compounds and such compositions, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR2 is involved.

IN THE CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 USC §371of International PCT Patent Application No. PCT/EP2007/052442, filedMar. 15, 2007.

This application is a U.S. national phase application under 35 USC 371of international application number PCT/EP2008/052768, filed Mar. 7,2008, which claims priority to European application No. 07103654.5,filed Mar. 7, 2007; PCT International Application No. PCT/EP2007/052442,filed Mar. 15, 2007; and European application No. 07116403.2, filed Sep.14, 2007, which are hereby incorporated herein by reference in theirentirety for all purposes.

FIELD OF THE INVENTION

The present invention relates to novel pyridin-2-one-derivatives whichare positive allosteric modulators of the metabotropic glutamatereceptor subtype 2 (“mGluR2”) and which are useful for the treatment orprevention of neurological and psychiatric disorders associated withglutamate dysfunction and diseases in which the mGluR2 subtype ofmetabotropic receptors is involved. The invention is also directed topharmaceutical compositions comprising such compounds, to processes toprepare such compounds and such compositions, and to the use of suchcompounds for the prevention or treatment of neurological andpsychiatric disorders and diseases in which mGluR2 is involved.

BACKGROUND OF THE INVENTION

Glutamate is the major amino acid neurotransmitter in the mammaliancentral nervous system. Glutamate plays a major role in numerousphysiological functions, such as learning and memory but also sensoryperception, development of synaptic plasticity, motor control,respiration, and regulation of cardiovascular function. Furthermore,glutamate is at the centre of several different neurological andpsychiatric diseases, where there is an imbalance in glutamatergicneurotransmission.

Glutamate mediates synaptic neurotransmission through the activation ofionotropic glutamate receptors channels (iGluRs), and the NMDA, AMPA andkainate receptors which are responsible for fast excitatorytransmission.

In addition, glutamate activates metabotropic glutamate receptors(mGluRs) which have a more modulatory role that contributes to thefine-tuning of synaptic efficacy.

Glutamate activates the mGluRs through binding to the largeextracellular amino-terminal domain of the receptor, herein called theorthosteric binding site. This binding induces a conformational changein the receptor which results in the activation of the G-protein andintracellular signalling pathways.

The mGluR2 subtype is negatively coupled to adenylate cyclase viaactivation of Gαi-protein, and its activation leads to inhibition ofglutamate release in the synapse. In the central nervous system (CNS),mGluR2 receptors are abundant mainly throughout cortex, thalamicregions, accessory olfactory bulb, hippocampus, amygdala,caudate-putamen and nucleus accumbens.

Activating mGluR2 was shown in clinical trials to be efficacious totreat anxiety disorders. In addition, activating mGluR2 in variousanimal models was shown to be efficacious, thus representing a potentialnovel therapeutic approach for the treatment of schizophrenia, epilepsy,addiction/drug dependence, Parkinson's disease, pain, sleep disordersand Huntington's disease.

To date, most of the available pharmacological tools targeting mGluRsare orthosteric ligands which activate several members of the family asthey are structural analogs of glutamate.

A new avenue for developing selective compounds acting at mGluRs is toidentify compounds that act through allosteric mechanisms, modulatingthe receptor by binding to a site different from the highly conservedorthosteric binding site.

Positive allosteric modulators of mGluRs have emerged recently as novelpharmacological entities offering this attractive alternative. Variouscompounds have been described as mGluR2 positive allosteric modulators.

WO2004/092135 (NPS & Astra Zeneca), WO2004/018386, WO2006/014918 andWO2006/015158 (Merck), WO2001/56990 (Eli Lilly) and WO2006/030032 (Addex& Janssen Pharmaceutica) describe respectively phenyl sulfonamide,acetophenone, indanone, pyridylmethyl sulfonamide and pyridinonederivatives as mGluR2 positive allosteric modulators. None of thespecifically disclosed compounds are structurally related to thecompounds of the invention.

WO2007/104783 describes 1,4-disubstituted 3-cyano-pyridone-derivativesthat are positive allosteric modulators of metabotropicreceptors-subtype 2 (“mGluR2”).

It was demonstrated that such compounds do not activate the receptor bythemselves. Rather, they enable the receptor to produce a maximalresponse to a concentration of glutamate which by itself induces aminimal response. Mutational analysis has demonstrated unequivocallythat the binding of mGluR2 positive allosteric modulators does not occurat the orthosteric site, but instead at an allosteric site situatedwithin the seven transmembrane region of the receptor.

Animal data are suggesting that positive allosteric modulators of mGluR2have effects in anxiety and psychosis models similar to those obtainedwith orthosteric agonists. Allosteric modulators of mGluR2 were shown tobe active in fear-potentiated startle, and in stress-inducedhyperthermia models of anxiety. Furthermore, such compounds were shownto be active in reversal of ketamine- or amphetamine-inducedhyperlocomotion, and in reversal of amphetamine-induced disruption ofprepulse inhibition of the acoustic startle effect models ofschizophrenia (J. Pharmacol. Exp. Ther. 2006, 318, 173-185;Psychopharmacology 2005, 179, 271-283).

Recent animal studies further reveal that the selective positiveallostric modulator of metabotropic glutamate receptor subtype 2biphenyl-indanone (BINA) blocks a hallucinogenic drug model ofpsychosis, supporting the strategy of targeting mGluR2 receptors fortreating glutamatergic dysfunction in schizophrenia (Mol. Pharmacol.2007, 72, 477-484).

Positive allosteric modulators enable potentiation of the glutamateresponse, but they have also been shown to potentiate the response toorthosteric mGluR2 agonists such as LY379268 or DCG-IV. These dataprovide evidence for yet another novel therapeutic approach to treatabove mentioned neurological and psychiatric diseases involving mGluR2,which would use a combination of a positive allosteric modulator ofmGluR2 together with an orthosteric agonist of mGluR2.

The present compounds are characterized by a central pyridine-2-onemoiety substituted in position 3 with cyano and in position 4 withoptionally substituted phenyl which is in turn substituted, in position4, via a linker with optionally substituted tetrahydropyran. The presentcompounds are potent positive allosteric mGluR2 modulators.

DESCRIPTION OF THE INVENTION

The invention relates to compounds having metabotropic glutamatereceptor 2 modulator activity. The present invention provides a compoundaccording to formula (I),

including any stereochemically isomeric form thereof, wherein

-   R₁ is C₄₋₆alkyl, or C₁₋₃alkyl substituted with C₃₋₇cycloalkyl;-   R₂ is hydrogen, halo or trifluoromethyl;-   R₃ is hydrogen or C₁₋₄alkyl substituted with hydroxyl;-   X is O or NH;-   n is an integer of value 1 or 2;    or a pharmaceutically acceptable salt or a solvate thereof.

The present invention also relates to the use of a compound of formula(I) or any subgroup thereof for the manufacture of a medicament fortreating or preventing, in particular for treating, a condition in amammal, including a human, the treatment or prevention of which isaffected or facilitated by the neuromodulatory effect of an allostericmodulator of mGluR2, in particular a positive allosteric modulator.

An embodiment of the present invention are those compounds of formula(I)

including any stereochemically isomeric form thereof, wherein

-   R₁ is C₄₋₆alkyl, or C₁₋₃alkyl substituted with C₃₋₇cycloalkyl;-   R₂ is hydrogen, halo or trifluoromethyl;-   R₃ is hydrogen or C₁₋₄alkyl substituted with hydroxyl;-   X is O or NH;-   n is an integer of value 1 or 2;    or a pharmaceutically acceptable salt or a solvate thereof;    provided that the compound is other than

R₂

H

2-F

2-F

3-F

3-Cl

An embodiment of the present invention are those compounds of formula(I) wherein R₁ is C₄₋₆alkyl, in particular C₄₋₅alkyl, such as forexample 1-butyl, 2-methyl-1-propyl, 3-methyl-1-butyl; in particular1-butyl or 3-methyl-1-butyl.

An embodiment of the present invention are those compounds of formula(I) wherein R₁ is C₁₋₃alkyl substituted with C₃₋₇cycloalkyl, inparticular cyclopropylmethyl or 2-(cyclopropyl)-1-ethyl, more inparticular cyclopropylmethyl.

An embodiment of the present invention are those compounds of formula(I) or any subgroup thereof as mentioned hereinbefore as embodiment,wherein R₂ is hydrogen.

An embodiment of the present invention are those compounds of formula(I) or, whenever possible, any subgroup thereof as mentionedhereinbefore as embodiment, wherein R₂ is halo, in particular fluoro orchloro.

An embodiment of the present invention are those compounds of formula(I) or, whenever possible, any subgroup thereof as mentionedhereinbefore as embodiment, wherein R₂ is trifluoromethyl.

An embodiment of the present invention are those compounds of formula(I) or, whenever possible, any subgroup thereof as mentionedhereinbefore as embodiment, wherein R₃ is hydrogen.

An embodiment of the present invention are those compounds of formula(I) or, whenever possible, any subgroup thereof as mentionedhereinbefore as embodiment, wherein R₃ is C₁₋₄alkyl substituted withhydroxyl; in particular wherein R₃ is CH₂OH.

An embodiment of the present invention are those compounds of formula(I) or, whenever possible, any subgroup thereof as mentionedhereinbefore as embodiment, wherein X is O.

An embodiment of the present invention are those compounds of formula(I) or, whenever possible, any subgroup thereof as mentionedhereinbefore as embodiment, wherein X is NH.

An embodiment of the present invention are those compounds of formula(I) or, whenever possible, any subgroup thereof as mentionedhereinbefore as embodiment, wherein n is 1.

An embodiment of the present invention are those compounds of formula(I) or, whenever possible, any subgroup thereof as mentionedhereinbefore as embodiment, wherein n is 2.

An embodiment of the present invention are those compounds of formula(I) or, whenever possible, any subgroup thereof as mentionedhereinbefore as embodiment, wherein n is 1 and R₂ is other than hydrogenand said R₂ is placed in meta position compared to the pyridinonemoiety.

An embodiment of the present invention are those compounds of formula(I) or, whenever possible, any subgroup thereof as mentionedhereinbefore as embodiment, wherein n is 1 and R₂ is other than hydrogenand said R₂ is placed in ortho position compared to the pyridinonemoiety.

An embodiment of the present invention are those compounds of formula(I), wherein R₁ is C₄₋₆alkyl, in particular 1-butyl or 3-methyl-1-butyl;or C₁₋₃alkyl substituted with C₃₋₇cycloalkyl, in particularcyclopropylmethyl or 2-(cyclopropyl)-1-ethyl;

-   R₂ is hydrogen, fluoro, chloro or trifluoromethyl;-   R₃ is hydrogen;-   n is 1.

An embodiment of the present invention are those compounds of formula(I) selected from,

R₂

3-F

3-Cl

3-CF₃

3-Cl

3-Cl

3-Cl

3-CF₃

H

2-F

2-F

3-F

3-Cl

or a pharmaceutically acceptable salt thereof or a solvate thereof.

An embodiment of the present invention are those compounds of formula(I) selected from,

R₂

3-F

3-Cl

3-CF₃

3-Cl

3-Cl

3-Cl

3-CF₃

or a pharmaceutically acceptable salt thereof or a solvate thereof.

As used hereinbefore or hereinafter, the notation C₁₋₃alkyl as a groupor part of a group defines a saturated, straight or branched,hydrocarbon radical having from 1 to 3 carbon atoms, such as methyl,ethyl, 1-propyl and 1-methyl-1-ethyl. Preferably C₁₋₃alkyl representsmethyl.

As used hereinbefore or hereinafter, the notation C₁₋₄alkyl as a groupor part of a group defines a saturated, straight or branched,hydrocarbon radical having from 1 to 4 carbon atoms such as methyl,ethyl, propyl, 1-methyl-1-ethyl, 1-butyl, 2-methyl-1-propyl. Preferably,C₁₋₄alkyl represents methyl.

As used hereinbefore or hereinafter, the notation C₄₋₆alkyl as a groupor part of a group defines a saturated, straight or branched,hydrocarbon radical having from 4 to 6 carbon atoms such as 1-butyl,2-methyl-1-propyl, 1-pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 1-hexyland the like. Preferably C₄₋₆alkyl represents 1-butyl.

As used hereinbefore or hereinafter, the notation C₄₋₅alkyl as a groupor part of a group defines a saturated, straight or branched,hydrocarbon radical having 4 or 5 carbon atoms such as 1-butyl,2-methyl-1-propyl, 1-pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl and thelike.

As used hereinbefore or hereinafter, the notation C₃₋₇cycloalkyl definesa saturated, cyclic hydrocarbon radical having from 3 to 7 carbon atoms,such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl. Preferably C₃₋₇cycloalkyl represents cyclopropyl.

As used hereinbefore or hereinafter, the notation halo is generic tofluoro, chloro, bromo and iodo.

For therapeutic use, salts of the compounds of formula (I) are thosewherein the counterion is pharmaceutically acceptable. However, salts ofacids and bases which are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whetherpharmaceutically acceptable or not, are included within the ambit of thepresent invention.

The pharmaceutically acceptable salts are defined to comprise thetherapeutically active non-toxic acid addition salt forms that thecompounds according to formula (I) are able to form. Said salts can beobtained by treating the base form of the compounds according to formula(I) with appropriate acids, for example inorganic acids, for examplehydrohalic acid, in particular hydrochloric acid, hydrobromic acid,sulphuric acid, nitric acid and phosphoric acid; organic acids, forexample acetic acid, hydroxyacetic acid, propanoic acid, lactic acid,pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid,fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonicacid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,cyclamic acid, salicylic acid, p-aminosalicylic acid and pamoic acid.

Conversely said acid salt forms can be converted into the free base formby treatment with an appropriate base.

The compounds according to formula (I) containing acidic protons mayalso be converted into their therapeutically active non-toxic base saltforms by treatment with appropriate organic and inorganic bases.Appropriate base salt forms comprise, for example, the ammonium salts,the alkaline and earth alkaline metal salts, in particular lithium,sodium, potassium, magnesium and calcium salts, salts with organicbases, e.g. the benzathine, N-methyl-D-glucamine, hybramine salts, andsalts with amino acids, for example arginine and lysine.

Conversely, said base salt forms can be converted into the free acidforms by treatment with an appropriate acid.

The pharmaceutically acceptable acid addition salt forms of thecompounds of formula (I) are the preferred pharmaceutically acceptablesalt forms of the compounds of formula (I).

The term solvate comprises the solvent addition forms as well as thepharmaceutically acceptable salts thereof, which the compounds offormula (I) are able to form. Examples of such solvent addition formsare e.g. hydrates, alcoholates and the like.

It will be appreciated that some of the compounds of formula (I) andtheir salts and solvates may contain one or more centers of chiralityand exist as stereochemically isomeric forms.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible isomeric forms that the compounds of formula (I) maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of compounds denotes the mixture of all possiblestereochemically isomeric forms, said mixtures containing alldiastereomers and enantiomers of the basic molecular structure. But theinvention also embraces each of the individual isomeric forms of formula(I) and their salts or solvates, substantially free, i.e. associatedwith less than 10%, preferably less than 5%, in particular less than 2%and most preferably less than 1% of the other isomers. Thus, when acompound of formula (I) is for instance specified as (R), this meansthat the compound is substantially free of the (S) isomer.

In particular, stereogenic centers may have the R- or S-configuration;substituents on bivalent cyclic (partially) saturated radicals may haveeither the cis- or trans-configuration.

Following CAS nomenclature conventions, when two stereogenic centers ofknown absolute configuration are present in a compound, an R or Sdescriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) tothe lowest-numbered chiral center, the reference center. Theconfiguration of the second stereogenic center is indicated usingrelative descriptors [R*,R*] or [R*,S*], where R* is always specified asthe reference center and [R*,R*] indicates centers with the samechirality and [R*,S*] indicates centers of unlike chirality. Forexample, if the lowest-numbered chiral center in the compound has an Sconfiguration and the second center is R, the stereo descriptor would bespecified as S—[R*,S*]. If “α” and “β” are used: the position of thehighest priority substituent on the asymmetric carbon atom in the ringsystem having the lowest ring number, is arbitrarily always in the “α”position of the mean plane determined by the ring system. The positionof the highest priority substituent on the other asymmetric carbon atomin the ring system (hydrogen atom in compounds according to Formula (I))relative to the position of the highest priority substituent on thereference atom is denominated “α”, if it is on the same side of the meanplane determined by the ring system, or “β”, if it is on the other sideof the mean plane determined by the ring system.

Whenever used hereinafter, the term “compounds of formula (I)” or anysubgroup thereof, is meant to also include their stereochemicallyisomeric forms, their pharmaceutically acceptable salts and theirsolvates. Of special interest are those compounds of formula (I) whichare stereochemically pure.

In the framework of this application, an element, in particular whenmentioned in relation to a compound according to formula (I), comprisesall isotopes and isotopic mixtures of this element, either naturallyoccurring or synthetically produced, either with natural abundance or inan isotopically enriched form. In particular, when hydrogen ismentioned, it is understood to refer to ¹H, ²H, ³H or mixtures thereof;when carbon is mentioned, it is understood to refer to ¹¹C, ¹²C, ¹³C,¹⁴C or mixtures thereof; when nitrogen is mentioned, it is understood torefer to ¹³N, ¹⁴N, ¹⁵N or mixtures thereof; when oxygen is mentioned, itis understood to refer to ¹⁴O, ¹⁵O, ¹⁶O, ¹⁷O, ¹⁸O or mixtures thereof;and when fluor is mentioned, it is understood to refer to ¹⁸F, ¹⁹F ormixtures thereof. The compounds according to the invention thereforealso comprise compounds with one or more isotopes of one or moreelement, and mixtures thereof, including radioactive compounds, alsocalled radio labelled compounds, wherein one or more non-radioactiveatoms has been replaced by one of its radioactive isotopes. Inparticular, the radioactive atom is selected from the group of hydrogen,carbon, nitrogen, sulfur, oxygen and halogen. Preferably, theradioactive atom is selected from the group of hydrogen, carbon andhalogen. In particular, the radioactive isotope is selected from thegroup of ³H, ¹¹C, ¹⁸F, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and⁸²Br. Preferably, the radioactive isotope is selected from the group of³H, ¹¹C and ¹⁸F.

Whenever used hereinbefore or hereinafter that substituents can beselected each independently out of a list of definitions, all possiblecombinations are intended which are chemically possible.

Lines drawn from substituents into ring systems indicate that the bondmay be attached to any of the suitable ring atoms.

In general, compounds of formula (I) can be prepared according to thebelow Experimental procedure 1.

EXPERIMENTAL PROCEDURE 1

Compounds of formula (I) can be prepared by reacting an intermediate offormula (II) wherein Y represents a group suitable for Pd mediatedcoupling with boronic acids or boronic esters, such as, for example, ahalo or triflate, with an intermediate of formula (III) wherein R₄ andR₅ represent hydrogen or C₁₋₄alkyl, or wherein R₄ and R₅ may be takentogether to form for example the bivalent radical of formula —CH₂CH₂—,—CH₂CH₂CH₂—, or —C(CH₃)₂C(CH₃)₂—, according to Reaction Scheme (1). Thereaction may be performed in a suitable reaction-inert solvent, such as,for example, 1,4-dioxane or mixtures of inert solvents such as, forexample, 1,4-dioxane/DMF, in the presence of a suitable base, such as,for example, aqueous NaHCO₃ or Na₂CO₃, a suitable catalyst, such as forexample a Pd-complex catalyst such as, for example, Pd(PPh₃)₄, underthermal conditions such as, for example, heating the reaction mixture at150° C. under microwave irradiation, during for example 10 minutes. InReaction Scheme (1), all variables are defined as in formula (I) or asdefined hereinabove.

The compounds of formula (I) and some of the intermediates in thepresent invention may contain an asymmetric carbon atom. Purestereochemically isomeric forms of said compounds and said intermediatescan be obtained by the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, chiral liquid chromatography and the like methods.Enantiomers can be obtained from racemic mixtures by first convertingsaid racemic mixtures with suitable resolving agents such as, forexample, chiral acids, to mixtures of diastereomeric salts or compounds;then physically separating said mixtures of diastereomeric salts orcompounds by, for example, selective crystallization or chromatographictechniques, e.g. liquid chromatography and the like methods; and finallyconverting said separated diastereomeric salts or compounds into thecorresponding enantiomers. Pure stereochemically isomeric forms may alsobe obtained from the pure stereochemically isomeric forms of theappropriate intermediates and starting materials, provided that theintervening reactions occur stereospecifically.

An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) and intermediates involves liquidchromatography or SCF (Super Critical Fluid) chromatography, inparticular using a chiral stationary phase.

Some of the intermediates and starting materials are known compounds andmay be commercially available or may be prepared according to art-knownprocedures.

The intermediates can also be prepared according to the belowExperimental procedures 2 to 11.

EXPERIMENTAL PROCEDURE 2

Intermediates of formula (II) wherein Y represents halo, saidintermediates being represented by formula (II-a), can be prepared byreacting an intermediate of formula (IV) with a suitable halogenatingagent such as, for example, P(═O)Br₃. The reaction may be performed in asuitable reaction-inert solvent such as, for example, DMF, at amoderately elevated temperature such as, for example, 110° C. InReaction Scheme (3), all variables are defined as in formula (I).

EXPERIMENTAL PROCEDURE 3

Intermediates of formula (II) wherein Y represents triflate, saidintermediates being represented by formula (II-b), can be prepared byreacting an intermediate of formula (IV) with triflic anhydride (alsocalled trifloromethanesulfonic anhydride) according to Reaction Scheme(4). The reaction may be performed in a suitable reaction-inert solventsuch as, for example, dichloromethane, in the presence of a suitablebase such as, for example, pyridine at a low temperature such as, forexample, −78° C. In Reaction Scheme (3), all variables are defined as informula (I).

EXPERIMENTAL PROCEDURE 4

Intermediates of formula (IV) can be prepared by art-known procedures byreacting an intermediate of formula (V) with a suitable reagent formethylether-cleavage, such as, for example, NaOH, in a suitable solventsuch as, for example, water, at a moderately high temperature such as,for example, 100° C. In Reaction Scheme (4), all variables are definedas in formula (I).

EXPERIMENTAL PROCEDURE 5

Intermediates of formula (V) can be prepared by art-known procedures byreacting commercially available4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile with an alkylatingagent of formula (VI), such as, for example, cyclopropylmethylbromide,according to Reaction Scheme (5). The reaction may be performed in aninert solvent such as, for example, acetonitrile, using a suitable basesuch as, for example, K₂CO₃, and, optionally an iodine salt such as, forexample, KI, at a moderately high temperature such as, for example, 120°C. In Reaction Scheme (5), all variables are defined as in formula (I)and Z is a suitable leaving group such as, for example, halo, e.g.bromo.

EXPERIMENTAL PROCEDURE 6

Intermediates of formula (III) can be prepared by art-known proceduresby reacting an intermediate of formula (VII) wherein halo may representchloro, bromo or iodo, with a suitable boron source such as, forexample, bis(pinacolato)diboron, in the presence of a suitable catalyst,such as a palladium catalyst, such as, for example,1,1′-bis(diphenylphosphino)ferrocenepalladium(II)dichloride, accordingto Reaction Scheme (6). The reaction may be performed in an inertsolvent such as, for example, dichloromethane, in the presence of asuitable salt such as, for example, potassium acetate, at moderatelyhigh temperature such as, for example, 110° C., during for example 16hours.

Alternatively, intermediates of formula (III) can also be prepared byart-known procedures of metal-halogen exchange and subsequent reactionwith an appropriate boron source from intermediates of formula (VII).Thus for example, reaction of an intermediate of formula (VII) with anorganolithium compound such as, for example, n-butyllithium, at amoderately low temperature such as, for example, ±40° C., in an inertsolvent such as, for example, THF, followed by subsequent reaction withan appropriate boron source such as, for example, trimethoxyborane.

In Reaction Scheme (6), all variables are defined as in formula (I), andR₄ and R₅ are as defined hereinabove.

EXPERIMENTAL PROCEDURE 7

Intermediates of formula (VII) wherein X represents NH and R₃ representshydrogen, said intermediates being represented by formula (VII-a), canbe prepared by art-known procedures by reacting an aniline intermediateof formula (VIII-a) with tetrahydro-4H-pyran-4-one according to ReactionScheme (7). The reaction may be performed in the presence of a suitablereducing agent, such as for example, sodium hydride, in an inert solventsuch as, for example, 1,2-dichloroethane, at moderately low temperaturesuch as, for example, 25° C. during for example 3 days. In ReactionScheme (7), all variables are defined as in formula (I) and halo may bechloro, bromo or iodo.

EXPERIMENTAL PROCEDURE 8

Intermediates of formula (VII) wherein X represents O and R₃ representshydrogen, said intermediates being represented by formula (VII-b), canbe prepared by art-known procedures by reacting a phenol intermediate offormula (VIII-b) with tetrahydro-4-pyranol according to Reaction Scheme(8). The reaction may be performed in the presence of a phosphine, suchas for example triphenylphosphine, and a suitable coupling agent forMitsunobu-like couplings, such as for example di-tert-butylazodicarboxylate, in an inert solvent such as, for example,dichloromethane, at moderately low temperature such as, for example, 25°C. during for example 2 hours. In Reaction Scheme (8), all variables aredefined as in formula (I) and halo may be chloro, bromo or iodo.

EXPERIMENTAL PROCEDURE 9

Intermediates of formula (VII) can also be prepared by art-knownprocedures from an aniline-like intermediate of formula (IX) via aSandmeyer type reaction according to Reaction Scheme (9). In ReactionScheme (9), all variables are defined as in formula (I) and halo may bechloro, bromo or iodo.

EXPERIMENTAL PROCEDURE 10

Intermediates of formula (IX) can be prepared by art-known proceduresfrom a nitro intermediate of formula (X) via reduction of the nitrogroup to the amino function by art-know procedures such as catalytichydrogenation or the use of tin(II) chloride dihydrate as a reductingagent, according to Reaction Scheme (10). In Reaction Scheme (10), allvariables are defined as in formula (I) and halo may be chloro, bromo oriodo.

EXPERIMENTAL PROCEDURE 11

Intermediates of formula (X) can be prepared by art-known procedures byreacting an intermediate of formula (XI) with a suitabletetrahydropyranyl intermediate of formula (XII), such as, for example,tetrahydro-4-pyranol, according to Reaction Scheme (11). The reactionmay be performed in the presence of a suitable base such as, forexample, cesium carbonate, in an inert solvent such as, for example,tetrahydrofuran, at moderately high temperature such as, for example,140° C., during for example 16 hours. In Reaction Scheme (11), allvariables are defined as in formula (I) and halo may be chloro, bromo oriodo.

Pharmacology

The compounds provided in this invention are positive allostericmodulators of metabotropic glutamate receptors, in particular they arepositive allosteric modulators of mGluR2. The compounds of the presentinvention do not appear to bind to the glutamate recognition site, theorthosteric ligand site, but instead to an allosteric site within theseven transmembrane region of the receptor. In the presence of glutamateor an agonist of mGluR2, the compounds of this invention increase themGluR2 response. The compounds provided in this invention are expectedto have their effect at mGluR2 by virtue of their ability to increasethe response of such receptors to glutamate or mGluR2 agonists,enhancing the response of the receptor. Hence, the present inventionrelates to a compound according to the present invention for use as amedicine, as well as to the use of a compound according to the inventionor a pharmaceutical composition according to the invention for themanufacture of a medicament for treating or preventing, in particulartreating, a condition in a mammal, including a human, the treatment orprevention of which is affected or facilitated by the neuromodulatoryeffect of allosteric modulators of mGluR2, in particular positiveallosteric modulators thereof. The present invention also relates to acompound according to the present invention or a pharmaceuticalcomposition according to the invention for use in the manufacture of amedicament for treating or preventing, in particular treating, acondition in a mammal, including a human, the treatment or prevention ofwhich is affected or facilitated by the neuromodulatory effect ofallosteric modulators of mGluR2, in particular positive allostericmodulators thereof. The present invention also relates to a compoundaccording to the present invention or a pharmaceutical compositionaccording to the invention for treating or preventing, in particulartreating, a condition in a mammal, including a human, the treatment orprevention of which is affected or facilitated by the neuromodulatoryeffect of allosteric modulators of mGluR2, in particular positiveallosteric modulators thereof.

Also, the present invention relates to the use of a compound accordingto the invention or a pharmaceutical composition according to theinvention for the manufacture of a medicament for treating, preventing,ameliorating, controlling or reducing the risk of various neurologicaland psychiatric disorders associated with glutamate dysfunction in amammal, including a human, the treatment or prevention of which isaffected or facilitated by the neuromodulatory effect of positiveallosteric modulators of mGluR2.

Where the invention is said to relate to the use of a compound orcomposition according to the invention for the manufacture of amedicament for e.g. the treatment of a mammal, it is understood thatsuch use is to be interpreted in certain jurisdictions as a method ofe.g. treatment of a mammal, comprising administering to a mammal in needof such e.g. treatment, an effective amount of a compound or compositionaccording to the invention.

In particular, the neurological and psychiatric disorders associatedwith glutamate dysfunction, include one or more of the followingconditions or diseases: acute neurological and psychiatric disorderssuch as, for example, cerebral deficits subsequent to cardiac bypasssurgery and grafting, stroke, cerebral ischemia, spinal cord trauma,head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronaldamage, dementia (including AIDS-induced dementia), Alzheimer's disease,Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage,retinopathy, cognitive disorders, idiopathic and drug-inducedParkinson's disease, muscular spasms and disorders associated withmuscular spasticity including tremors, epilepsy, convulsions, migraine(including migraine headache), urinary incontinence, substancetolerance, substance withdrawal (including substances such as, forexample, opiates, nicotine, tobacco products, alcohol, benzodiazepines,cocaine, sedatives, hypnotics, etc.), psychosis, schizophrenia, anxiety(including generalized anxiety disorder, panic disorder, and obsessivecompulsive disorder), mood disorders (including depression, mania,bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus,macular degeneration of the eye, emesis, brain edema, pain (includingacute and chronic states, severe pain, intractable pain, neuropathicpain, and post-traumatic pain), tardive dyskinesia, sleep disorders(including narcolepsy), attention deficit/hyperactivity disorder, andconduct disorder.

In particular, the present invention relates to the use of a compound offormula (I) for the manufacture of a medicament for treating orpreventing, in particular for treating, a central nervous systemdisorder selected from the group of anxiety disorders, psychoticdisorders, personality disorders, substance-related disorders, eatingdisorders, mood disorders, migraine, epilepsy or convulsive disorders,childhood disorders, cognitive disorders, neurodegeneration,neurotoxicity and ischemia.

Preferably, the central nervous system disorder is an anxiety disorder,selected from the group of agoraphobia, generalized anxiety disorder(GAD), obsessive-compulsive disorder (OCD), panic disorder,posttraumatic stress disorder (PTSD), social phobia and other phobias.

Preferably, the central nervous system disorder is a psychotic disorderselected from the group of schizophrenia, delusional disorder,schizoaffective disorder, schizophreniform disorder andsubstance-induced psychotic disorder

Preferably, the central nervous system disorder is a personalitydisorder selected from the group of obsessive-compulsive personalitydisorder and schizoid, schizotypal disorder.

Preferably, the central nervous system disorder is a substance-relateddisorder selected from the group of alcohol abuse, alcohol dependence,alcohol withdrawal, alcohol withdrawal delirium, alcohol-inducedpsychotic disorder, amphetamine dependence, amphetamine withdrawal,cocaine dependence, cocaine withdrawal, nicotine dependence, nicotinewithdrawal, opioid dependence and opioid withdrawal.

Preferably, the central nervous system disorder is an eating disorderselected from the group of anorexia nervosa and bulimia nervosa.

Preferably, the central nervous system disorder is a mood disorderselected from the group of bipolar disorders (I & II), cyclothymicdisorder, depression, dysthymic disorder, major depressive disorder andsubstance-induced mood disorder.

Preferably, the central nervous system disorder is migraine.

Preferably, the central nervous system disorder is epilepsy or aconvulsive disorder selected from the group of generalized nonconvulsiveepilepsy, generalized convulsive epilepsy, petit mal status epilepticus,grand mal status epilepticus, partial epilepsy with or withoutimpairment of consciousness, infantile spasms, epilepsy partialiscontinua, and other forms of epilepsy.

Preferably, the central nervous system disorder isattention-deficit/hyperactivity disorder.

Preferably, the central nervous system disorder is a cognitive disorderselected from the group of delirium, substance-induced persistingdelirium, dementia, dementia due to HIV disease, dementia due toHuntington's disease, dementia due to Parkinson's disease, dementia ofthe Alzheimer's type, substance-induced persisting dementia and mildcognitive impairment.

Of the disorders mentioned above, the treatment of anxiety,schizophrenia, migraine, depression, and epilepsy are of particularimportance.

At present, the fourth edition of the Diagnostic & Statistical Manual ofMental Disorders (DSM-IV) of the American Psychiatric Associationprovides a diagnostic tool for the identification of the disordersdescribed herein. The person skilled in the art will recognize thatalternative nomenclatures, nosologies, and classification systems forneurological and psychiatric disorders described herein exist, and thatthese evolve with medical and scientific progresses.

Because such positive allosteric modulators of mGluR2, includingcompounds of formula (I), enhance the response of mGluR2 to glutamate,it is an advantage that the present methods utilize endogenousglutamate.

Because positive allosteric modulators of mGluR2, including compounds offormula (I), enhance the response of mGluR2 to agonists, it isunderstood that the present invention extends to the treatment ofneurological and psychiatric disorders associated with glutamatedysfunction by administering an effective amount of a positiveallosteric modulator of mGluR2, including compounds of formula (I), incombination with an mGluR2 agonist.

The compounds of the present invention may be utilized in combinationwith one or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of formula (I) or the other drugs may have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone.

Pharmaceutical Compositions

The invention also relates to a pharmaceutical composition comprising apharmaceutically acceptable carrier or diluent and, as activeingredient, a therapeutically effective amount of a compound accordingto the invention, in particular a compound according to formula (I),including a stereochemically isomeric form thereof, or apharmaceutically acceptable salt thereof or a solvate thereof.

The compounds according to the invention, in particular the compoundsaccording to formula (I), including a stereochemically isomeric formthereof, or a pharmaceutically acceptable salt thereof or a solvatethereof, or any subgroup or combination thereof may be formulated intovarious pharmaceutical forms for administration purposes. As appropriatecompositions there may be cited all compositions usually employed forsystemically administering drugs.

To prepare the pharmaceutical compositions of this invention, aneffective amount of the particular compound, optionally in salt form, asthe active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier or diluent, which carrier or diluentmay take a wide variety of forms depending on the form of preparationdesired for administration. These pharmaceutical compositions aredesirable in unitary dosage form suitable, in particular, foradministration orally, rectally, percutaneously, by parenteral injectionor by inhalation. For example, in preparing the compositions in oraldosage form, any of the usual pharmaceutical media may be employed suchas, for example, water, glycols, oils, alcohols and the like in the caseof oral liquid preparations such as, for example, suspensions, syrups,elixirs, emulsions and solutions; or solid carriers such as, forexample, starches, sugars, kaolin, diluents, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. Because of the ease in administration, oraladministration is preferred, and tablets and capsules represent the mostadvantageous oral dosage unit forms in which case solid pharmaceuticalcarriers are obviously employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable suspensions may also be preparedin which case appropriate liquid carriers, suspending agents and thelike may be employed. Also included are solid form preparations that areintended to be converted, shortly before use, to liquid formpreparations. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notintroduce a significant deleterious effect on the skin. Said additivesmay facilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weight,sex, extent of disorder and general physical condition of the particularpatient as well as other medication the individual may be taking, as iswell known to those skilled in the art. Furthermore, it is evident thatsaid effective daily amount may be lowered or increased depending on theresponse of the treated subject and/or depending on the evaluation ofthe physician prescribing the compounds of the instant invention.

Depending on the mode of administration, the pharmaceutical compositionwill comprise from 0.05 to 99% by weight, preferably from 0.1 to 70% byweight, more preferably from 0.1 to 50% by weight of the activeingredient, and, from 1 to 99.95% by weight, preferably from 30 to 99.9%by weight, more preferably from 50 to 99.9% by weight of apharmaceutically acceptable carrier, all percentages being based on thetotal weight of the composition.

As already mentioned, the invention also relates to a pharmaceuticalcomposition comprising the compounds according to the invention and oneor more other drugs in the treatment, prevention, control, amelioration,or reduction of risk of diseases or conditions for which compounds ofFormula (I) or the other drugs may have utility as well as to the use ofsuch a composition for the manufacture of a medicament. The presentinvention also relates to a combination of a compound according to thepresent invention and a mGluR2 orthosteric agonist. The presentinvention also relates to such a combination for use as a medicine. Thepresent invention also relates to a product comprising (a) a compoundaccording to the present invention, a pharmaceutically acceptable saltthereof or a solvate thereof, and (b) a mGluR2 orthosteric agonist, as acombined preparation for simultaneous, separate or sequential use in thetreatment or prevention of a condition in a mammal, including a human,the treatment or prevention of which is affected or facilitated by theneuromodulatory effect of mGluR2 allosteric modulators, in particularpositive mGluR2 allosteric modulators. The different drugs of such acombination or product may be combined in a single preparation togetherwith pharmaceutically acceptable carriers or diluents, or they may eachbe present in a separate preparation together with pharmaceuticallyacceptable carriers or diluents.

The following examples are intended to illustrate but not to limit thescope of the present invention.

EXPERIMENTAL PART

Several methods for preparing the compounds of this invention areillustrated in the following Examples. Unless otherwise noted, allstarting materials were obtained from commercial suppliers and usedwithout further purification. Specifically, the following abbreviationsmay be used in the examples and throughout the specification:

DCM (dichloromethane) DMF (dimethylformamide) Et₂O (diethyl ether) EtOAc(ethyl acetate) g (grams) HPLC (High Pressure Liquid Chromatography)LCMS (Liquid Chromatography Mass Spectrum) MeOH (methanol) MHz(megahertz) ml (milliliters) min (minutes) mmol (millimol) Pd(PPh₃)₄(tetrakis(triphenylphosphine)palladium(0)) THF (tetrahydrofuran)

All references to brine refer to a saturated aqueous solution of NaCl.Unless otherwise indicated, all temperatures are expressed in ° C.(degrees Celsius). All reactions were not conducted under an inertatmosphere at room temperature, unless otherwise noted.

Microwave assisted reactions were performed in a single-mode reactor:Emrys™ Optimizer microwave reactor (Personal Chemistry A.B., currentlyBiotage) or in a multimode reactor: MicroSYNTH Labstation (Milestone,Inc.).

A. Preparation of the Intermediates Example A.1 Methanesulfonic acid2-cyclopropyl-ethyl ester (intermediate 1)

To a solution of 2-cyclopropyl-ethanol (15.1 g, 175.3 mmol) andtriethylamine (48.6 ml, 350.6 mmol) in dichloromethane (300 ml), at 0°C., was added methanesulfonyl chloride (20.35 ml, 262.9 mmol) dropwiseand the mixture was then stirred at room temperature for 2 hours. Waterwas added and layers were separated. The organic phase was dried(Na₂SO₄) and evaporated in vacuo to yield crude intermediate 1 (100%)used without further purification.

Example A.21-Cyclopropylmethyl-4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile(intermediate 2)

To a solution of 4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile(12.2 g, 81.48 mmol) in acetonitrile (250 ml) were addedbromomethyl-cyclopropane (11 g, 81.48 mmol) and potassium carbonate(22.48 g, 162.9 mmol) and the mixture was heated at 110° C. for 24hours. The mixture was cooled to room temperature and the solid wasfiltered off The filtrate was evaporated till dryness and the resultingcrude residue was then triturated with diethylether to yield pureintermediate 2 (15.72 g, 94%) as a white solid.

Example A.31-(2-Cyclopropyl-ethyl)-4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile(intermediate 3)

To a solution of 4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile(19.81 g, 131.98 mmol) in acetonitrile (520 ml) were added intermediate1 (34.36 g, 171.57 mmol) and potassium carbonate (56.73 g, 410.3 mmol)and the mixture was heated at 105° C. for 12 hours. The mixture wascooled to room temperature and the solid was filtered off The filtratewas evaporated till dryness. The crude product was purified by columnchromatography (silica gel; DCM to DCM/EtOAc up to 20% as eluent). Thedesired fractions were collected and evaporated in vacuo to yieldintermediate 3 (13.18 g, 46%).

Example A.4 1-Butyl-4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile(intermediate 4)

To a solution of 4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (20g, 133 mmol) in acetonitrile (800 ml) were added 1-bromobutane (15.8 ml,146 mmol) and potassium carbonate (36.7 g, 266 mmol) and the mixture washeated at 110° C. for 24 hours. The mixture was cooled to roomtemperature and the solid was filtered off The filtrate was evaporatedtill dryness and the resulting crude residue was then triturated withdiethylether to yield pure intermediate 4 (27.39 g, >99%) as a whitesolid.

Example A.51-Cyclopropylmethyl-4-hydroxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile(intermediate 5)

Intermediate 2 (15.7 g, 76.8 mmol) was added at room temperature to a 1Naqueous solution of sodium hydroxide (300 ml) and THF (50 ml). Thereaction mixture was heated at 140° C. (oil bath temperature) for 16hours. The mixture was cooled to room temperature and the THF was mostlyevaporated in vacuo. The aqueous layer was cooled to 0° C. and acidifiedby the addition of aqueous 2N HCl, adjusting the pH to about 3, at whichpoint a white solid precipitated. The solid was filtered off, washedwith Et₂O and dried in vacuo to yield intermediate 5 as a white solid(10.44 g, 71%) that was used without further purification.

Example A.61-(2-Cyclopropyl-ethyl)-4-hydroxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile(intermediate 6)

Intermediate 3 (13.18 g, 60.4 mmol) was added at room temperature to a0.5N aqueous solution of sodium hydroxide (221 ml). The reaction mixturewas heated at 110° C. (oil bath temperature) for 12 hours. The mixturewas cooled to 0° C. and acidified by the addition of aqueous 2N HCl,adjusting the pH to about 3, at which point a white solid precipitated.The solid was filtered off, washed with Et₂O and dried in vacuo to yieldintermediate 6 as a white solid (11.24 g, 91%) that was used withoutfurther purification.

Example A.7 1-Butyl-4-hydroxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile(intermediate 7)

Intermediate 4 (27.39 g, 133 mmol) was added at room temperature to a 1Naqueous solution of sodium hydroxide (500 ml) and THF (100 ml). Thereaction mixture was heated at 110° C. (oil bath temperature) for 24hours. The mixture was cooled to room temperature and the solvent wasevaporated in vacuo until the volume was reduced to approximately 250ml. The aqueous layer was then cooled to 0° C. and acidified by theaddition of aqueous 2N HCl, adjusting the pH to about 3, at which pointa white solid precipitated. The solid was filtered off, washed with Et₂Oand dried in vacuo to yield intermediate 7 as a white solid (25 g, 98%)that was used without further purification.

Example A.84-Bromo-1-cyclopropylmethyl-2-oxo-1,2-dihydro-pyridine-3-carbonitrile(intermediate 8)

To a solution of intermediate 5 (10.4 g, 54.67 mmol) in DMF (250 ml) wasadded phosphorus(III) oxybromide (31.3 g, 109.3 mmol) and the mixturewas heated at 110° C. for 1.5 hours. After cooling in an ice bath thesolution was partitioned between water and EtOAc. After threeextractions with EtOAc the combined organic fractions were washed withbrine, dried over MgSO₄ and the solvent evaporated in vacuo. The crudeproduct was purified by column chromatography (silica gel; DCM aseluent). The desired fractions were collected and evaporated in vacuo toyield intermediate 8 (8.83 g, 64%).

Example A.94-Bromo-1-(2-cyclopropyl-ethyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile(intermediate 9)

To a solution of intermediate 6 (6.0 g, 29.37 mmol) in DMF (150 ml) wasadded phosphorus(III) oxybromide (16.84 g, 58.75 mmol) and the mixturewas heated at 110° C. for 3 hours. After cooling in an ice bath thesolution was partitioned between water and EtOAc. After threeextractions with EtOAc the combined organic fractions were washed withbrine, dried over Na₂SO₄ and the solvent evaporated in vacuo. The crudeproduct was purified by column chromatography (silica gel; DCM aseluent). The desired fractions were collected and evaporated in vacuo toyield intermediate 9 (7.0 g, 89%).

Example A.10 4-Bromo-1-butyl-2-oxo-1,2-dihydro-pyridine-3-carbonitrile(intermediate 10)

To a solution of intermediate 7 (39 g, 203 mmol) in DMF (600 ml) wasadded phosphorus(III) oxybromide (116 g, 406 mmol) and the mixture washeated at 110° C. for 1.5 hours. After cooling in an ice bath thesolution was partitioned between water and EtOAc. After threeextractions with EtOAc the combined organic fractions were washed withbrine, dried over Na₂SO₄ and the solvent evaporated in vacuo. The crudeproduct was purified by column chromatography (silica gel; DCM aseluent). The desired fractions were collected and evaporated in vacuo toyield intermediate 10 (36.7 g, 72%).

Example A.11 (4-Bromo-2-fluoro-phenyl)-(tetrahydro-pyran-4-yl)-amine(intermediate 11)

A mixture of 4-bromo-2-fluoro-phenylamine (1 g, 5.26 mmol),tetrahydro-4H-pyran-4-one (0.73 ml, 7.89 mmol), and sodiumtriacetoxyborohydride (1.66 g, 7.89 mmol) in 1,2-dichloroethane (50 ml)was stirred at room temperature for 72 hours. The mixture was filteredthrough a diatomaceous earth pad. The diatomaceous earth pad was washedwith dichloromethane. The combined filtrates were washed with NaHCO₃(aqueous saturated solution), dried over Na₂SO₄ and evaporated tilldryness. The crude product thus obtained was purified by columnchromatography (silica gel; DCM to DCM/MeOH(NH₃) up to 5%). The desiredfractions were collected and evaporated in vacuo to yield intermediate11 as a yellow oil (1.44 g, 100%).

Example A.12 (4-Bromo-2-chloro-phenyl)-(tetrahydro-pyran-4-yl)-amine(intermediate 12)

A mixture of 4-bromo-2-chloro-phenylamine (4 g, 19.37 mmol),tetrahydro-4H-pyran-4-one (2.69 ml, 29.05 mmol), oven dried molecularsieves 4 Å (2 g) and sodium triacetoxyborohydride (6.12 g, 29.05 mmol)in 1,2-dichloroethane (100 ml) was stirred at room temperature for 72hours. The mixture was filtered through a diatomaceous earth pad. Thediatomaceous earth pad was washed with dichloromethane. The combinedfiltrates were washed with NaHCO₃ (aqueous saturated solution), driedover Na₂SO₄ and evaporated till dryness. The crude product thus obtainedwas purified by column chromatography (silica gel; DCM to DCM/MeOH(NH₃)up to 5%). The desired fractions were collected and evaporated in vacuoto yield intermediate 12 as a brown oil (4.83 g, 86%).

Example A.13(4-Bromo-2-trifluoromethyl-phenyl)-(tetrahydro-pyran-4-yl)-amine(intermediate 13)

A mixture of 4-bromo-2-trifluoromethyl-phenylamine (0.88 g, 3.66 mmol),tetrahydro-4H-pyran-4-one (0.5 ml, 5.49 mmol), oven dried molecularsieves 4 Å (1 g) and sodium triacetoxyborohydride (1.15 g, 5.49 mmol) in1,2-dichloroethane (30 ml) was stirred at room temperature for 72 hours.The mixture was filtered through a diatomaceous earth pad. Thediatomaceous earth pad was washed with dichloromethane. The combinedfiltrates were washed with NaHCO₃ (aqueous saturated solution), driedover Na₂SO₄ and evaporated till dryness. The crude product thus obtainedwas purified by column chromatography (silica gel; DCM to DCM/MeOH(NH₃)up to 5%). The desired fractions were collected and evaporated in vacuoto yield intermediate 13 as a yellow oil (1.11 g, 99%).

Example A.14 4-(4-Bromo-2-chloro-phenoxy)-tetrahydro-pyran (intermediate14)

A mixture of 4-bromo-2-chloro-phenol (4 g, 19.28 mmol),tetrahydro-4-pyranol (2.20 ml, 23.13 mmol) and polymer supportedtriphenylphosphine (17.29 g, 39.29 mmol; purchased from Argonaut,loading 2.23 mmol/g) was suspended in dichloromethane (250 ml) and thencooled to 0° C. Di-tent-butyl azadicarboxylate (6.65 g, 28.92 mmol) wasadded portionwise and the reaction mixture was warmed to roomtemperature and shaken for 2 hours. The resin was filtered off andwashed with dichloromethane. The combined filtrates were evaporated tilldryness. The crude product thus obtained was purified by columnchromatography (silica gel; DCM to DCM/MeOH(NH₃) up to 2%). The desiredfractions were collected and evaporated in vacuo to yield intermediate14 as a colorless oil (5.38 g, 95%).

Example A.15[2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-(tetrahydro-pyran-4-yl)-amine(intermediate 15)

To a solution of intermediate 11 (0.7 g, 2.55 mmol) in 1,4-dioxane (4.5ml) and DMF (0.5 ml) were added bis(pinacolato)diboron (0.77 g, 3.06mmol) and potassium acetate (0.75 g, 7.65 mmol). The mixture wasdegassed and then[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II); complexwith DCM (1:1) (0.062 g, 0.07 mmol) was added. The reaction mixture washeated at 150° C. for 10 minutes under microwave irradiation. Aftercooling to room temperature the mixture was filtered through a pad ofdiatomaceous earth. The diatomaceous earth was washed with EtOAc. Thecombined organic extracts were washed with brine, dried over Na₂SO₄, andthe solvent evaporated in vacuo to afford the desired boronateintermediate 15 (100%) as a crude that was used without furtherpurification.

Example A.16[2-Chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-(tetrahydro-pyran-4-yl)-amine(intermediate 16)

To a solution of intermediate 12 (2 g, 6.88 mmol) in 1,4-dioxane (10.8ml) and DMF (1.2 ml) were added bis(pinacolato)diboron (2.09 g, 8.25mmol) and potassium acetate (2.02 g, 20.64 mmol). The mixture wasdegassed and then[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II); complexwith DCM (1:1) (0.16 g, 0.2 mmol) was added. The reaction mixture washeated at 150° C. for 10 minutes under microwave irradiation. Aftercooling to room temperature the mixture was filtered through a pad ofdiatomaceous earth. The diatomaceous earth was washed with EtOAc. Thecombined organic extracts were washed with brine, dried over Na₂SO₄, andthe solvent evaporated in vacuo to afford the desired boronateintermediate 16 (100%) as a crude that was used without furtherpurification.

Example A.17(Tetrahydropyran-4-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-trifluoromethyl-phenyl]-amine(intermediate 17)

To a solution of intermediate 13 (1.11 g, 3.42 mmol) in 1,4-dioxane (4.5ml) and DMF (0.5 ml) were added bis(pinacolato)diboron (1.04 g, 4.1mmol) and potassium acetate (1.00 g, 10.26 mmol). The mixture wasdegassed and then[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II); complexwith DCM (1:1) (0.083 g, 0.1 mmol) was added. The reaction mixture washeated at 150° C. for 10 minutes under microwave irradiation. Aftercooling to room temperature the mixture was filtered through a pad ofdiatomaceous earth. The diatomaceous earth was washed with EtOAc. Thecombined organic extracts were washed with brine, dried over Na₂SO₄, andthe solvent evaporated in vacuo to afford the desired boronateintermediate 17 (100%) as a crude that was used without furtherpurification.

Example A.184-[2-Chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-tetrahydro-pyran(intermediate 18)

To a solution of intermediate 14 (2 g, 6.85 mmol) in 1,4-dioxane (10.8ml) and DMF (1.2 ml) were added bis(pinacolato)diboron (2.01 g, 8.23mmol) and potassium acetate (2.01 g, 20.55 mmol). The mixture wasdegassed and then[1,1′-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II); complexwith DCM (1:1) (0.16 g, 0.2 mmol) was added. The reaction mixture washeated at 150° C. for 10 minutes under microwave irradiation. Aftercooling to room temperature the mixture was filtered through a pad ofdiatomaceous earth. The diatomaceous earth was washed with EtOAc. Thecombined organic extracts were washed with brine, dried over Na₂SO₄, andthe solvent evaporated in vacuo to afford the desired boronateintermediate 18 (100%) as a crude that was used without furtherpurification.

B. Preparation of the Final Compounds Example B.11-Cyclopropylmethyl-4-[3-fluoro-4-(tetrahydro-pyran-4-ylamino)-phenyl]-2-oxo-1,2-dihydro-pyridine-3-carbonitrile(compound 1)

To a solution of intermediate 15 (0.8 g, 2.55 mmol) in 1,4-dioxane (3ml) and a saturated solution of Na₂CO₃ (3 ml) was added intermediate 8(0.58 g, 2.31 mmol). The resulting solution was degassed using a streamof nitrogen and to this was added Pd(PPh₃)₄ (0.26 mg, 0.23 mmol). Thereaction was then microwaved in a sealed tube at 150° C. for 10 minutes.The resulting cooled reaction mixture was then diluted with EtOAc andfiltered through a pad of diatomaceous earth. The filtrate was washedwith brine, dried over Na₂SO₄ and concentrated in vacuo. The crudereaction mixture was then purified by column chromatography (silica gel;DCM to DCM/EtOAc up to 30% as eluent). The desired fractions werecollected and evaporated in vacuo to yield compound 1 (0.241 g, 30%).

Example B.21-Cyclopropylmethyl-4-[3-chloro-4-(tetrahydro-pyran-4-ylamino)-phenyl]-2-oxo-1,2-dihydro-pyridine-3-carbonitrile(compound 2)

To a solution of intermediate 16 (0.57 g, 1.7 mmol) in 1,4-dioxane (2ml) and a saturated solution of Na₂CO₃ (2 ml) was added intermediate 8(0.43 g, 1.7 mmol). The resulting solution was degassed using a streamof nitrogen and to this was added Pd(PPh₃)₄ (0.19 mg, 0.17 mmol). Thereaction was then microwaved in a sealed tube at 150° C. for 10 minutes.The resulting cooled reaction mixture was then diluted with EtOAc andfiltered through a pad of diatomaceous earth. The filtrate was washedwith brine, dried over Na₂SO₄ and concentrated in vacuo. The crudereaction mixture was then purified by column chromatography (silica gel;DCM to DCM/EtOAc up to 30% as eluent). The desired fractions werecollected and evaporated in vacuo to yield compound 2 (0.103 g, 16%).

Example B.31-Cyclopropylmethyl-2-oxo-4-[4-(tetrahydro-pyran-4-ylamino)-3-trifluoromethyl-phenyl]-1,2-dihydro-pyridine-3-carbonitrile(compound 3)

To a solution of intermediate 17 (0.63 g, 1.69 mmol) in 1,4-dioxane (3ml) and a saturated solution of Na₂CO₃ (3 ml) was added intermediate 8(0.42 g, 1.69 mmol). The resulting solution was degassed using a streamof nitrogen and to this was added Pd(PPh₃)₄ (0.19 mg, 0.17 mmol). Thereaction was then microwaved in a sealed tube at 150° C. for 10 minutes.The resulting cooled reaction mixture was then diluted with EtOAc andfiltered through a pad of diatomaceous earth. The filtrate was washedwith brine, dried over Na₂SO₄ and concentrated in vacuo. The crudereaction mixture was then purified by column chromatography (silica gel;DCM to DCM/EtOAc up to 30% as eluent). The desired fractions werecollected and evaporated in vacuo to yield compound 3 (0.59 g, 9%).

Example B.44-[3-Chloro-4-(tetrahydro-pyran-4-yloxy)-phenyl]-1-(2-cyclopropyl-ethyl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile(compound 4)

To a solution of intermediate 18 (0.57 g, 1.7 mmol) in 1,4-dioxane (2ml) and a saturated solution of Na₂CO₃ (2 ml) was added intermediate 9(0.45 g, 1.7 mmol). The resulting solution was degassed using a streamof nitrogen and to this was added Pd(PPh₃)₄ (0.19 mg, 0.17 mmol). Thereaction was then microwaved in a sealed tube at 150° C. for 10 minutes.The resulting cooled reaction mixture was then diluted with EtOAc andfiltered through a pad of diatomaceous earth. The filtrate was washedwith brine, dried over Na₂SO₄ and concentrated in vacuo. The crudereaction mixture was then purified by column chromatography (silica gel;DCM to DCM/EtOAc up to 30% as eluent). The desired fractions werecollected and evaporated in vacuo to yield compound 4 (0.108 g, 17%).

Table 1 lists compounds of formula (I) that were prepared according toone of the above Examples (Ex. no.).

TABLE 1

Co. Exp. no. no.

R₂

1 B1

3-F

2 B2

3-Cl

3 B3

3-CF₃

4 B4

3-Cl

5 B4

3-Cl

6 B1

3-Cl

7 B3

3-CF₃

8 B1

H

9 B4

2-F

10 B1

2-F

11 B1

3-F

12 B1

3-Cl

C. Analytical Part

For LCMS-characterization of the compounds of the present invention, thefollowing method was used.

LCMS—General Procedure

The HPLC measurement was performed using a HP 1100 from AgilentTechnologies comprising a pump (quaternary or binary) with degasser, anautosampler, a column oven, a diode-array detector (DAD) and a column asspecified in the respective methods below. Flow from the column wassplit to a MS detector. The MS detector was configured with anelectrospray ionization source. Nitrogen was used as the nebulizer gas.The source temperature was maintained at 140° C. Data acquisition wasperformed with MassLynx-Openlynx software.

Method 1

In addition to the general procedure: Reversed phase HPLC was carriedout on an XDB-C18 cartridge (1.8 μm, 2.1×30 mm) from Agilent, with aflow rate of 1 ml/min, at 60° C. The gradient conditions used are: 90% A(0.5 g/l ammonium acetate solution), 5% B (acetonitrile), 5% C(methanol) to 50% B and 50% C in 6.5 minutes, to 100% B at 7 minutes andequilibrated to initial conditions at 7.5 minutes until 9.0 minutes.Injection volume 2 μl. High-resolution mass spectra (Time of Flight,TOF) were acquired only in positive ionization mode by scanning from 100to 750 in 0.5 seconds using a dwell time of 0.1 seconds. The capillaryneedle voltage was 2.5 kV and the cone voltage was 20 V.Leucine-Enkephaline was the standard substance used for the lock masscalibration.

Method 2

In addition to the general procedure: Reversed phase HPLC was carriedout on an ACE-C18 column (3.0 μm, 4.6×30 mm) from AdvancedChromatography Technologies, with a flow rate of 1.5 ml/min, at 40° C.The gradient conditions used are: 80% A (0.5 g/l ammonium acetatesolution), 10% B (acetonitrile), 10% C (methanol) to 50% B and 50% C in6.5 minutes, to 100% B at 7 minutes and equilibrated to initialconditions at 7.5 minutes until 9.0 minutes. Injection volume 5 μl.High-resolution mass spectra (Time of Flight, TOF) were acquired only inpositive ionization mode by scanning from 100 to 750 in 0.5 secondsusing a dwell time of 0.1 seconds. The capillary needle voltage was 2.5kV for positive ionization mode and the cone voltage was 20 V.Leucine-Enkephaline was the standard substance used for the lock masscalibration.

Melting Point Determination

Melting point determinations were performed on a Mettler FP62 apparatus.

TABLE 2 Analytical data (R_(t) means retention time in minutes; (MH)⁺means the protonated mass of the compound (free base) Comp. MeltingPoint LCMS No. (° C.) (MH)⁺ R_(t) (min) method 1 249.5 368 3.56 1 2decomposes 384 3.81 1 3 decomposes 418 4.17 1 4 decomposes 399 4.26 1 5nd 401 4.58 1 6 >300 398 4.20 1 7 nd 432 4.44 1 8 195 352 3.64 1 9 136371 4.04 2 10 nd 384 4.22 2 11 nd 384 4.21 1 12 decomposes 400 4.48 1 ndmeans not determined

D. Pharmacological Examples

The compounds provided in the present invention are positive allostericmodulators of mGluR2. These compounds appear to potentiate glutamateresponses by binding to an allosteric site other than the glutamatebinding site. The response of mGluR2 to a concentration of glutamate isincreased when compounds of formula (I) are present. Compounds offormula (I) are expected to have their effect substantially at mGluR2 byvirtue of their ability to enhance the function of the receptor. Thebehaviour of positive allosteric modulators tested at mGluR2 using the[³⁵S]GTPγS binding assay method described below and which is suitablefor the identification of such compounds, and more particularly thecompounds according to formula (I), are shown in Table 3.

[³⁵S]GTPγS Binding Assay

The [³⁵S]GTPγS binding assay is a functional membrane-based assay usedto study G-protein coupled receptor (GPCR) function wherebyincorporation of a non-hydrolysable form of GTP, [³⁵S]GTPγS (guanosine5′-triphosphate, labelled with gamma-emitting ³⁵S), is measured. TheG-protein 7 subunit catalyzes the exchange of guanosine 5′-diphosphate(GDP) by guanosine triphosphate (GTP) and on activation of the GPCR byan agonist, [³⁵S]GTPγS, becomes incorporated and cannot be cleaved tocontinue the exchange cycle (Harper (1998) Current Protocols inPharmacology 2.6.1-10, John Wiley & Sons, Inc.). The amount ofradioactive [³⁵S]GTPγS incorporation is a direct measure of the activityof the G-protein and hence the activity of the agonist can bedetermined. mGluR2 receptors are shown to be preferentially coupled toGγi-protein, a preferential coupling for this method, and hence it iswidely used to study receptor activation of mGluR2 receptors both inrecombinant cell lines and in tissues (Schaffhauser et al 2003,Pinkerton et al, 2004, Mutel et al (1998) Journal of Neurochemistry.71:2558-64; Schaffhauser et al (1998) Molecular Pharmacology 53:228-33).Here we describe the use of the [³⁵S]GTPγS binding assay using membranesfrom cells transfected with the human mGluR2 receptor and adapted fromSchaffhauser et al ((2003) Molecular Pharmacology 4:798-810) for thedetection of the positive allosteric modulation (PAM) properties of thecompounds of this invention.

Membrane Preparation

CHO-cells were cultured to pre-confluence and stimulated with 5 mMbutyrate for 24 hours, prior to washing in PBS, and then collection byscraping in homogenisation buffer (50 mM Tris-HCl buffer, pH 7.4, 4°C.). Cell lysates were homogenized briefly (15s) using an ultra-turraxhomogenizer. The homogenate was centrifuged at 23 500×g for 10 minutesand the supernatant discarded. The pellet was resuspended in 5 mMTris-HCl, pH 7.4 and centrifuged again (30 000×g, 20 min, 4° C.). Thefinal pellet was resuspended in 50 mM HEPES, pH 7.4 and stored at −80°C. in appropriate aliquots before use. Protein concentration wasdetermined by the Bradford method (Bio-Rad, USA) with bovine serumalbumin as standard.

[³⁵S]GTPγS Binding Assay

Measurement of mGluR2 positive allosteric modulatory activity of testcompounds in membranes containing human mGluR2 was performed usingfrozen membranes that were thawed and briefly homogenised prior topre-incubation in 96-well microplates (15 μg/assay well, 30 minutes, 30°C.) in assay buffer (50 mM HEPES pH 7.4, 100 mM NaCl, 3 mM MgCl₂, 50 μMGDP, 10 μg/ml saponin,) with increasing concentrations of positiveallosteric modulator (from 0.3 nM to 50 μM) and either a minimalpre-determined concentration of glutamate (PAM assay), or no addedglutamate. For the PAM assay, membranes were pre-incubated withglutamate at EC₂₅ concentration, i.e. a concentration that gives 25% ofthe maximal response glutamate, and is in accordance to published data(Pin et al. (1999) Eur. J. Pharmacol. 375:277-294). After addition of[³⁵S]GTPγS (0.1 nM, f.c.) to achieve a total reaction volume of 200 μl,microplates were shaken briefly and further incubated to allow[³⁵S]GTPγS incorporation on activation (30 minutes, 30° C.). Thereaction was stopped by rapid vacuum filtration over glass-fibre filterplates (Unifilter 96-well GF/B filter plates, Perkin-Elmer, DownersGrove, USA) microplate using a 96-well plate cell harvester (Filtermate,Perkin-Elmer, USA), and then by washing three times with 300 μl ofice-cold wash buffer (Na₂PO₄.2H₂O 10 mM, NaH₂PO₄.H₂O 10 mM, pH=7.4).Filters were then air-dried, and 40 μl of liquid scintillation cocktail(Microscint-O) was added to each well, and membrane-bound [³⁵S]GTPγS wasmeasured in a 96-well scintillation plate reader (Top-Count,Perkin-Elmer, USA). Non-specific [³⁵S]GTPγS binding is determined in thepresence of cold 10 μM GTP. Each curve was performed at least once usingduplicate sample per data point and at 11 concentrations.

Data Analysis

The concentration-response curves of representative compounds of thepresent invention in the presence of added EC₂₅ of mGluR2 agonistglutamate to determine positive allosteric modulation (PAM), weregenerated using the Prism GraphPad software (Graph Pad Inc, San Diego,USA). The curves were fitted to a four-parameter logistic equation(Y=Bottom+(Top-Bottom)/(1+10^((Log EC₅₀−X)*Hill Slope) allowingdetermination of EC₅₀ values. The EC₅₀ is the concentration of acompound that causes a half-maximal potentiation of the glutamateresponse. This is calculated by subtracting the maximal responses ofglutamate in presence of a fully saturating concentration of a positiveallosteric modulator from the response of glutamate in absence of apositive allosteric modulator. The concentration producing thehalf-maximal effect is then calculated as EC₅₀.

TABLE 3 Pharmacological data for compounds according to the invention.Compounds were tested in presence of mGluR2 agonist, glutamate at apredetermined EC₂₅ concentration, to determine positive allostericmodulation (GTPγS-PAM). Values shown are averages of duplicate values of11-concentration response curves, from at least one experiment. Alltested compounds showed a pEC₅₀ (−logEC₅₀) value of more than 5.0. Theerror of determination of a pEC₅₀ value for a single experiment isestimated to be about 0.3 log-units. GTPgS - hR2 PAM Comp. No. pEC₅₀ 1around 6 2 6.17 3 5.91 4 6.55 5 6.79 6 6.66 7 6.36 8 5.6 9 6.2 10 5.8 116.4 12 6.5

E. Composition Examples

“Active ingredient” as used throughout these examples relates to a finalcompound of formula (I), the pharmaceutically acceptable salts thereof,the solvates and the stereochemically isomeric forms thereof.

Typical examples of recipes for the formulation of the invention are asfollows:

1. Tablets

Active ingredient 5 to 50 mg Di-calcium phosphate 20 mg Lactose 30 mgTalcum 10 mg Magnesium stearate 5 mg Potato starchad 200 mg

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

2. Suspension

An aqueous suspension is prepared for oral administration so that each 1milliliter contains 1 to 5 mg of one of the active compounds, 50 mg ofsodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg ofsorbitol and water ad 1 ml.

3. Injectable

A parenteral composition is prepared by stirring 1.5% by weight ofactive ingredient of the invention in 10% by volume propylene glycol inwater.

4. Ointment

Active ingredient 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5 g Whitepetroleum 15 g Waterad 100 g

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

Reasonable variations are not to be regarded as a departure from thescope of the invention. It will be obvious that the thus describedinvention may be varied in many ways by those skilled in the art.

The invention claimed is:
 1. A compound of formula

including any stereochemically isomeric form thereof, wherein R₁ isC₄₋₆alkyl, or C₁₋₃alkyl substituted with C₃₋₇cycloalkyl; R₂ is hydrogen,halo or trifluoromethyl; R₃ is hydrogen or C₁₋₄alkyl substituted withhydroxyl; X is O or NH; n is an integer of value 1 or 2; or apharmaceutically acceptable salt thereof.
 2. A compound as claimed inclaim 1 wherein R₁ is C₄₋₆ alkyl.
 3. A compound as claimed in claim 2wherein R₁ is 1-butyl or 3-methyl-1-butyl.
 4. A compound as claimed inclaim 1 wherein R₁ is C₁₋₃ alkyl substituted with C₃₋₇ cycloalkyl.
 5. Acompound as claimed in claim 4 wherein R₁ is cyclopropylmethyl or2-(cyclopropyl)-1-ethyl.
 6. A compound as claimed in claim 1 wherein R₂is hydrogen or halo.
 7. A compound as claimed in claim 1 wherein R₂ istrifluoromethyl.
 8. A compound as claimed in claim 1 wherein R₃ ishydrogen.
 9. A compound as claimed in claim 1 wherein R₃ is C₁₋₄ alkylsubstituted with hydroxyl.
 10. A compound as claimed in claim 9 whereinR₃ is CH₂OH.
 11. A compound as claimed in claim 1 wherein X is O or NH.12. A compound as claimed in claim 1 wherein n is 1 or
 2. 13. A compoundas claimed in claim 1 wherein n is 1 and R₂ is other than hydrogen andsaid R₂ is placed in meta position compared to the pyridinone moiety.14. A compound as claimed in claim 1 wherein R₁ is 1-butyl,methyl-1-butyl, cyclopropylmethyl or 2-(cyclopropyl)-1-ethyl; R₂ ishydrogen, fluoro, chloro or trifluoromethyl; R₃ is hydrogen; n is
 1. 15.A compound as claimed in claim 1 wherein the compound is selected from

R₂

3-F

3-Cl

3-CF₃

3-Cl

3-Cl

3-Cl

3-CF₃

H

2-F

2-F

3-F

3-Cl

or a pharmaceutically acceptable salt thereof.
 16. A compound as claimedin claim 1 wherein the compound is selected from

R₂

3-F

3-Cl

3-CF₃

3-Cl

3-Cl

3-Cl

3-CF₃

or a pharmaceutically acceptable salt thereof.
 17. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundas claimed in claim 1 and a pharmaceutically acceptable carrier ordiluent.
 18. A process for preparing a compound as claimed in claim 1,comprising a) reacting an intermediate of formula (II) wherein Yrepresents a halo or triflate, with an intermediate of formula (III)wherein R₄ and R₅ represent hydrogen or C₁₋₄ alkyl, or wherein R₄ and R₅may be taken together to form the bivalent radical of formula —CH₂CH₂—,—CH₂CH₂CH₂—, or —C(CH₃)₂C(CH₃)₂—, in a suitable reaction-inert solvent,in the presence of a suitable base and a suitable catalyst, underthermal conditions

with R₁, R₂, R₃, X and n as defined in claim 1; or, if desired, furtherconverting compounds of formula (I) into each other following art-knowntransformations; or further, if desired, converting the compounds offormula (I), into a therapeutically active non-toxic acid addition saltby treatment with an acid, or conversely, converting the acid additionsalt form into the free base by treatment with alkali; or, if desired,preparing stereochemically isomeric forms thereof.